New formulation for retinoid-containing soft gelatin capsules

ABSTRACT

A new pharmaceutical formulation for retinoid-containing soft gelatin capsules is disclosed. The new formulation comprises a soft gelatin capsule filled with a fill mass comprising a retinoid as an active ingredient, a natural vegetable oil, a partially hydrogenated natural vegetable oil and medium chain triglycerides. Optionally, the new formulation also comprises a natural wax. In a particularly preferred embodiment, the soft gelatin capsule comprises pig gelatin in the capsule shell in combination with the above fill mass.

The present invention generally relates to a novel pharmaceuticalformulation for retinoids in the form of a soft gelatin capsule.

Retinoids are a class of compounds structurally related to vitamin A,comprising natural and synthetic compounds, which have been found to beclinically useful in dermatological, oncological and immunologicaldiseases.

The activity of retinoids is thought to be mediated by the nuclearretinoid receptors as for example the known retinoid receptors RARα, β,and γ or RXRα, β, and γ. The activity of the retinoids may be anagonistic or antagonistic activity. Retinoids with receptor agonisticactivity bind and activate receptors, whereas retinoids with receptorantagonistic activity bind receptors but do not activate them.

Specific examples for retinoids, which have been found to be clinicallyuseful, are for example all-trans retinoic acid which is known to beeffective in the treatment of acne, 13-cis retinoic acid which can beused in severe cases of acne (see Römpps Chemie Lexikon, 1987) or 9-cisretinoic acid, 9-cis retinal and 9-cis retinol as well as derivativesthereof, which are said to be clinically efficacious in the treatment ofT-helper cell type 1 mediated immune diseases (WO 99/09969).

The retinoids or pharmaceutically acceptable derivatives thereof cangenerally be administered either topically or systemically.

Oral pharmaceutical preparations of retinoids are known for example fromEP-A-0 552 624 A1, WO 00/25772 and WO 99/24024, describing tablets,sachets, aerosols for inhalation, soft and hard gelatin capsules.

A preferred oral dosage form is a soft gelatin capsule, as this materialis easily dissolved in the digestive tract. An overview on soft gelatincapsules is for example given in Soft Gelatin Capsules Development,Tabibi, S. E. and Gupta, S. L., Editor: Liu, Rong, Water-Insoluble DrugFormation (2000), pp. 609-633, Interpharm Press, Buffalo Grove, Ill.,USA. Moreover, in general, these preparations are favoured as theydisguise the unpleasant taste and obnoxious odours that may beassociated with the active pharmaceutical ingredient itself. They mayalso protect the active ingredient from oxygen and light induceddegradation.

EP-A-0 552 624 A1, for example, discloses a soft gelatin capsule with afill mass formulation consisting of 5-50 mg 9-cis retinoic acid, 1-3parts of oil, and 1-5 parts of a wax mixture.

Furthermore, WO 99/24024 discloses a specific retinoid-containing softgelatin capsule preparation containing 20 mg of active retinoidcompound, with 0.028 mg DL-α-tocopherol, 4.2 mg hydrogenated castor oil,56.00 mg caprylic/capric/stearic triglycerides, and 199.772 mg mediumchain triglycerides.

However, a crucial disadvantage of this formulation is that it exhibitsvery slow dissolution rates due to the formation of pellicles afterlong-term storage at temperatures above 5° C. This phenomenon increaseswith higher storage temperatures of the pharmaceutical preparation.Furthermore, in aqueous media, a non-dispersible fill mass and in somecases the formation of needles is observed.

Based on this state of the art, it is the object of the presentinvention to provide an improved retinoid-containing pharmaceutical softgelatin capsule formulation having significantly improved dissolutionproperties and/or showing no tendency for pellicle formation and/or theformation of a non-dispersible fill mass or needles.

According to the present invention, there is provided a novelpharmaceutical formulation according to claim 1, which comprises a softgelatin capsule filled with a fill mass comprising a retinoid as anactive ingredient, a natural vegetable oil, a partially hydrogenatednatural vegetable oil and medium chain triglycerides.

This novel formulation shows an excellent dissolution profile andneither pellicle formation nor a non-dispersible fill mass or needles asobserved in the previously used formulation described on page 19, lines14 ff. of WO 99/24024 mentioned above.

In a preferred embodiment of the present invention, the fill mass inaddition comprises a natural wax, especially preferred yellow wax, toenhance the viscosity thereof and in order to prevent the suspended drugfrom sedimentation within the capsule.

Further preferred, the fill mass may also contain an antioxidant toavoid oxidation of the active compound on the one hand as well as of thenatural oils on the other hand, and thus to increase the stability ofthe formulation.

The natural vegetable oil usable for the new formulation is preferablyselected from soybean oil, corn oil, sunflower oil, rape seed oil,linseed oil, sesame oil, olive oil, coconut oil, peanut oil, saffloweroil, castor oil and cottonseed oil or mixtures of two or more of theseoils. Soybean oil is especially preferred as it is well tolerated andwidely accepted.

The partially hydrogenated natural vegetable oils may also be selectedfrom the oils mentioned above.

The medium chain triglycerides are normally selected from triglyceridesof saturated fatty acids containing 8 to 10 carbon atoms, in particularfrom triglycerides of caprylic acid and/or capric acid.

The antioxidant is preferably selected from DL-α-tocopherol,butylhydroxy toluene (BHT) and butylhydroxy anisole (BHA).

The shell of the soft gelatin capsule normally comprises gelatin, one ormore plasticizers and water.

The plasticizers are preferably selected from the group consisting ofglycerol, sorbitol, propylene glycol, and mixtures of these components.More preferably, the plasticizers comprise a mixture of glycerol andsorbitol. The plasticizers are important to provide elasticity to thesoft gelatin capsules.

The gelatin used in the soft capsule shell preferably is pig gelatinwhich is in particular derived from pig skin.

According to the present invention it was found that there is anunexpected synergistic effect with regard to the dissolutioncharacteristics of the pharmaceutical formulation when pig gelatin inthe capsule shell is used in combination with the new fill massformulation. This effect was not observed when a combination of bovinegelatin with the new fill mass or pig gelatin with the previously usedfill mass of WO 99/24024 was used. However, also the new fill masscombined with bovine gelatin was superior compared to the combination ofbovine gelatin with the old fill mass.

In addition, the use of pig gelatin in this formulation also has theadvantage that it avoids regulatory issues associated with the use ofbovine gelatin, namely the occurrence of Bovine Transmissible SpongiformEncephalopathies.

The retinoid contained as active ingredient in the pharmaceuticalformulation can be selected from the group consisting of retinol,retinal, retinoic acid and derivatives thereof. Specific examples areall-trans retinol, all-trans retinoic acid, 13-cis retinoic acid and9-cis retinoic acid. The retinoids may also be present in the form ofpharmaceutically acceptable derivatives like salts, esters or prodrugs.

The fill mass contained in the soft gelatin capsule preferably comprisesabout 50 to 80 percent by weight, in particular about 60 to 70 percentby weight, especially preferred about 62 to 64 percent by weight, of thenatural vegetable oil, about 15 to 35 percent by weight, in particularabout 20 to 30 percent by weight, especially preferred about 24 to 25percent by weight, of the hydrogenated natural vegetable oil, and about3 to 20 percent by weight, in particular about 6 to 12 percent byweight, especially preferred about 8 to 9 percent by weight, of themedium chain triglycerides.

In cases where the fill mass also comprises a natural wax, the fill masspreferably comprises about 1 to 10 percent by weight, in particularabout 3 to 6 percent by weight, especially preferred about 4 percent byweight, of the natural wax, most preferred yellow wax.

Due to the above mentioned synergistic effect between fill mass andcapsule shell regarding the in-vitro dissolution characteristics, aparticularly preferred pharmaceutical formulation according to thepresent invention is a formulation comprising a soft gelatin capsuleshell containing pig gelatin, glycerol, sorbitol, and water, and a fillmass containing a retinoid, in particular 9-cis retinoic acid, as theactive ingredient, soybean oil, hydrogenated soybean oil, medium chaintriglycerides, yellow wax, and DL-α-tocopherol.

Other pharmaceutically acceptable additives like colorants, flavoringagents, stabilizers, emulsifying agents and so on may also be added, ifdesired.

The invention will now be described in greater detail by reference tothe following non-limiting examples.

EXAMPLES

Soft gelatin capsules according to the prior art and according to thepresent invention were produced in line with a standard manufacturingprocess schematically described below in compliance to cGMPrequirements. Each manufacturing step (as appropriate) was performedunder yellow light and inert atmosphere (nitrogen).

For manufacturing the fill mass, the triglyceride and oil components ofthe fill mass are weighed into a suitable stainless steel vessel, heatedto a maximum of 70° C., and cooled to room temperature at constantstirring. If applicable, an antioxidant, e.g. DL-α-tocopherol, is addedto the resulting mixture which is then stirred at room temperature forabout 30 minutes.

Subsequently, a retinoid, e.g. 9-cis retinoic acid, is added to theabove blend and stirred until a homogenous suspension is obtained. Thesuspension is stored in a stainless steel vessel under inert gas atreduced pressure, tightly sealed and protected from light untilencapsulation.

The encapsulation of the homogenous suspension into the gelatin shell isthen carried out on a rotary-dye machine as it is well known in theprior art (see for example Bauer, K. H. et al., Lehrbuch derPharmazeutischen Technologie, 6^(th) ed., pp. 343-348, Stuttgart, 1999)

Comparative Example 1 Batch A

A soft gelatin capsule formulation according to the prior art asdescribed in WO 99/24024 was prepared as outlined above, using thefollowing components for the fill mass and the capsule shell:

Old Fill Mass: Compound mg/capsule Alitretinoin (9-cis retinoic acid)20.00 DL-α-Tocopherol 0.028 Hydrogenated castor oil 4.200 Medium chaintriglycerides (Miglyol ® 812, 199.772 MCT) Caprylic/capric/stearictriglyceride 56.00 (Softisan ® 378, synthetic triglycerides)

Miglyol® 812 and Softisan® 378 were obtained from Sasol, Witten,Germany. DL-α-Tocopherol was from Roche Vitamins, Sisseln, Switzerland.Hydrogenated castor oil and alitretinoin were provided by HoffmannLa-Roche, Basel, Switzerland.

Capsule Shell: Compound mg/capsule Bovine Gelatin 80.85 Glycerol(98-101%) 24.53 Sorbitol, liquid, non-crystallizing 15.09* Water,purified 13.33** Iron oxide, red (E 172) 0.595 Iron oxide, yellow (E172) 0.595(*calculated as dry matter, **calculated amount in shell after drying)

In the Examples and Comparative Examples, all gelatins were obtainedfrom DGF Stoess, Eberbach, Germany, glycerol was from Uniquema,Emmerich, Germany, Sorbitol, liquid, non-crystallizing, was from Merck,Darmstadt, Germany, iron oxide red and yellow were obtained from BASF,Ludwigshafen, Germany, yellow wax was from Kahl, Trittau, Germany,soybean oil as well as partially hydrogenated soybean oil were fromFlorin, Muttenz, CH.

Dissolution tests were carried out with the prior art formulation ofComparative Example 1. It was found that the mixture Miglyol®812/Softisan® 378/hydrogenated castor oil exhibited problems indissolution testing due to the formation of pellicles after storage atelevated temperatures. Already after 1 week at 40° C., the fill mass wascovered in the dissolution test by a visible film. In addition, lumps ofa non-dispersible fill mass were observed.

A dissolution curve of a soft gelatin capsule according to ComparativeExample 1 (Batch A) is shown in FIG. 1. Even at optimised dissolutiontest conditions, the profile flattens out at higher temperatures, mostlikely due to the above mentioned effects. The dissolution rates forsamples stored at 40° C. already after 1 month rarely exceeded 20% (datanot shown).

Example 2 Batch D

A soft gelatin capsule formulation according to the present inventionwas prepared by the above described process, using the followingcomponents:

New fill mass according to the present invention: Compound mg/capsuleAlitretinoin (9-cis retinoic acid) 20 Soybean oil 162.00 Partiallyhydrogenated soybean oil 65.00 Medium chain triglycerides (Migyol ® 812)23.00 Yellow wax 10.00 DL-α-tocopherol 0.028

Capsule Shell: Compound mg/capsule Pig gelatin 82.0 Sorbitol, liquid,non-crystallizing 22.3* Glycerol (98-101%) 16.5 Water, purified 13.6**Iron oxide, red (E 172) 0.60 Iron oxide, yellow (E 172) 0.60(*calculated as dry matter, **calculated amount in shell after drying)

Example 3 Batch C

A further soft gelatin capsule formulation according to the presentinvention was prepared as in Example 2. However, while the fill mass wasidentical to the fill mass of Example 2, the capsule shell containedbovine gelatin instead of pig gelatin, and its composition was asfollows:

Capsule Shell: Compound mg/capsule Bovine gelatin 82.0 Sorbitol, liquid,non-crystallizing 15.3* Glycerol (98-101%) 26.4 Water, purified 14.6**Iron oxide, red (E 172) 0.60 Iron oxide, yellow (E 172) 0.60(*calculated as dry matter, **calculated amount in shell after drying)

Example 4 Batch E

A further soft gelatin capsule formulation according to the presentinvention was prepared using the fill mass of Example 2, except thatonly 5 mg alitretinoin were present and 15 mg additional soybean oilwere added instead, and the following composition for the capsule shell:

Capsule Shell: Compound mg/capsule Pig gelatin 82.0 Sorbitol, liquid,non-crystallizing 16.5* Glycerol (98-101%) 22.3 Water, purified 13.6**(*calculated as dry matter, **calculated amount in shell after drying)

The formulations according to Examples 2 to 4 were found to besufficiently stable for at least 12 months at temperatures up to 30° C.

Comparative Example 5 Batch B

A further soft gelatin capsule formulation based on the old fill massformulation of Comparative Example 1 was prepared using the capsuleshell composition of Example 2.

Dissolution tests with the formulations of Examples 2 to 4 (Batches D, Cand E) and Comparative Example 5 (Batch B) were carried out for samplesstored at 40° C./75% relative humidity (r.h.) to speed up the detectionof possible differences in the dissolution profiles of the variants. Thedissolution curves of the formulations of Examples 2 to 4 are shown inFIG. 2, and the dissolution curve of Comparative Example 5 is shown inFIG. 3.

Whereas the dissolution curve of Comparative Example 5 using the oldfill mass exhibited the same poor dissolution behaviour as ComparativeExample 1, the dissolution curves of Examples 2 to 4 showedsignificantly improved dissolution profiles. The new formulationsaccording to the present invention released the drug almost completelyin a short time in the same dissolution test set-up. These results couldbe reproduced even after 12 months storage under the same acceleratedstorage conditions.

Finally, the chemical stability of the active ingredient suspended inthe fill mass formulation of Comparative Example 1 as well as the one ofExample 2 were tested during a storage period of 6 months, and theamount of degradation products (including degradation products like13-cis retinoic acid and all-trans retinoic acid as well as unspecifieddegradation products) was determined. The comparative results of thestability test are shown in the following table.

Storage Conditions 6 months, 40° C./75% r.h. Fill mass from ComparativeFill mass Example 1 from Example 2 Total amount of degradation 1.49%0.98% products

As may be seen from this table, the total amount of degradation productscould be reduced from 1.49% for the formulation according to the priorart to 0.98% for the formulation according to the present invention.

In addition, the same stability test as described above was alsoconducted with fill mass formulations of Comparative Example 1 andExample 2 containing only 5 mg of the active ingredient instead of 20mg, together with 15 mg additional soybean oil (Comparative Example 1)or 15 mg additional Miglyol® 812 (Example 2). In this case, the totalamount of degradation products could even be reduced from 2.93% to 1.64%(corresponding to a reduction of about 50%).

This improved chemical stability is a further benefit of the newformulation according to the present invention.

1. Pharmaceutical formulation for retinoids comprising a soft gelatincapsule filled with a fill mass comprising a retinoid as an activeingredient, a natural vegetable oil, a partially hydrogenated naturalvegetable oil and medium chain triglycerides.
 2. (Originally Presented)Pharmaceutical formulation according to claim 1, wherein the fill massin addition comprises a natural wax.
 3. The pharmaceutial formulation ofclaim 1, wherein the fill mass in addition comprises an antioxidant. 4.The pharmaceutial formulation of claim 1, wherein the natural vegetableoil is selected from soybean oil, corn oil, sunflower oil, rape seedoil, linseed oil, sesame oil, olive oil, coconut oil, peanut oil,safflower oil, castor oil and cottonseed oil or mixtures of two or moreof these oils.
 5. The pharmaceutial formulation of claims 1, wherein thenatural vegetable oil is soybean oil.
 6. The pharmaceutial formulationof claim 1, wherein the medium chain triglycerides are selected fromtriglycerides of saturated fatty acids containing 8 to 10 carbon atoms.7. The pharmaceutial formulation of claim 2 wherein the natural wax isyellow wax.
 8. The pharmaceutial formulation of claim 3 wherein theantioxidant is selected from DL-α-tocopherol, butylhydroxy toluene (BHT)and butylhydroxy anisole (BHA).
 9. The pharmaceutial formulation ofclaim 1, wherein the capsule shell comprises gelatin, one or moreplasticizers and water.
 10. The pharmaceutial formulation of claim 9,wherein the plasticizer is selected from the group consisting ofglycerol, sorbitol, propylene glycol, and mixtures of these components.11. The pharmaceutial formulation of claim 10, wherein the plasticizercomprises a mixture of glycerol and sorbitol.
 12. The pharmaceutialformulation of claim 9, wherein the gelatin is pig gelatin, inparticular derived from pig skin.
 13. The pharmaceutial formulation ofclaims 1 wherein the retinoid is selected from the group consisting ofretinol, retinal, retinoic acid and derivatives thereof.
 14. Thepharmaceutial formulation of claim 13, wherein the retinoid is 9-cisretinoic acid.
 15. The pharmaceutial formulation of claim 1, wherein thefill mass comprises about 50 to 80 percent by weight of the naturalvegetable oil, about 15 to 35 percent by weight, of the hydrogenatednatural vegetable oil, and about 3 to 20 percent by weight, of themedium chain triglycerides.
 16. The pharmaceutial formulation of claim2, wherein the fill mass comprises about 1 to 10 percent by weight, ofthe natural wax.
 17. The pharmaceutial formulation of claim 15, whereinthe natural vegetable oil is soybean oil.
 18. The pharmaceutialformulation of claim 16, wherein the natural wax is yellow wax.
 19. Thepharmaceutical formulation of claim 6, wherein said saturated fatty acidis caprylic or capric acid.
 20. The pharmaceutical formulation of claim12, wherein said pig gelatin is derived from pig skin.
 21. Thepharmaceutical formulation of claim 15, wherein said fill mass comprisesfrom about 60 to 70 percent by weight of the natural vegetable oil andfrom about 20 to 30 percent by weight of the hydrogenated vegetable oiland from about 6 percent by weight to 12 percent by weight of the mediumchain triglycerides.
 22. The pharmaceutical formulation of claim 21,wherein said fill mass comprises 62 to 64 percent of weight of naturalvegetable oil, 24 to 25 percent by weight of hydrogenated naturalvegetable oil and from about 8 to 9 percent by weight of medium chaintriglycerides.
 23. The pharmaceutical formulation of claim 16, whereinthe fill mass comprises of about 3 to 6 percent weight of natural wax.24. The pharmaceutical formulation of claim 23, wherein the fill masscomprises from about 4 percent by weight of the natural wax.